JP2005538102A - Gelatin capsule showing reduced cross-linking - Google Patents

Abstract

The present invention relates to compositions suitable for use in the manufacture of gelatin capsules, gelatin capsules exhibiting reduced crosslinking, and methods of making such gelatin capsules.

Description

  The present invention relates to gelatin capsules that exhibit low gelatin cross-linking. Such capsules are particularly useful in the pharmaceutical, nutritional and food industries.

  Gelatin, a mixture of water-soluble proteins derived from collagen by hydrolysis, is widely used especially in the pharmaceutical and food industries. One major application of gelatin is in the manufacture of both hard and soft gelatin capsules. Such capsules are particularly desirable for their versatility (which contains solid, semi-solid, or liquid drug formulations) and their rapid dissolution characteristics. Unfortunately, drug dosage forms containing gelatin in the outer layer (eg, liquid or powder filled in gelatin capsules) are known to show a decrease in dissolution rate over time. This decrease in dissolution rate can lead to undesirable and unacceptable changes in in vitro dissolution profiles and bioavailability, particularly for drugs with poor water solubility or drugs whose absorption limits the dissolution rate. Such changes in the dissolution profile are believed to be the result of gelatin cross-linking occurring in the shell of the gelatin capsule.

  Singh et al., Alteration in Dissolution Characteristics of Gelatin-Containing Formulations, Pharmaceutical Technology, April 2002 (incorporated herein by reference in its entirety, but not included in the prior art) includes numbers containing glycerin, glycine and hydroxylamine hydrochloride. A report has been described that suggests that cross-linking of gelatin can be limited when seed reagents are introduced into the filled contents of gelatin capsules. Unfortunately, existing methods for the problem of gelatin cross-linking in capsule shells are unsatisfactory in situations where longer shelf life and stability are desired, especially through actual shelf life, shipping and processing conditions.

  If gelatin capsules that can provide predictable and stable dissolution rates after the capsules are stored under stress conditions can be produced, it is possible to orally administer drugs, particularly drugs that have low water solubility and limited absorption rates. Delivery will be a significant advance.

  The present invention provides compositions suitable for the manufacture of pharmaceutical capsule shells, as well as compositions comprising gelatin and a pharmaceutically acceptable sulfite compound.

  Desirably, the sulfite compound is present in an amount effective to inhibit gelatin crosslinking and / or pellicle formation in a capsule shell prepared from the composition.

  The composition of the present invention further provides a capsule shell.

  The present invention further provides a pharmaceutical dosage form comprising a capsule shell of the composition of the present invention that defines a fill volume at least partially occupied by the fill material.

  Desirably, the sulfite compound contained in the capsule shell of the pharmaceutical dosage form is present in an effective amount to inhibit gelatin crosslinking and / or film formation in the capsule shell.

  Desirably, the dosage form of the present invention contains a drug in the filler material, more preferably a drug with low water solubility.

  In one embodiment, the drug is a selective cyclooxygenase 2-inhibitor.

  The compositions and dosage forms of the present invention are particularly useful for liquid filling materials and soft gelatin capsules.

  The “thin film” here is a relatively water-insoluble film formed on the shell of a gelatin capsule, and the film tends to be thin, tough and rubbery. One mechanism underlying thin film formation is understood to be gelatin cross-linking. Gelatin cross-linking and thin film formation results in a decrease in dissolution rate. Thus, as described herein, the first capsule is stored in a reasonably short time after preparation and the second capsule is stored under stress conditions (eg, 4 weeks at 40 ° C. and 85% relative humidity in a sealed container). Subsequent quantification of the dissolution rate is meant to provide a means to evaluate film formation and / or gelatin cross-linking. The term “within reasonably short time from capsule preparation” means within a period such as one week depending on the storage conditions and storage period, where substantial cross-linking and / or film formation may not yet occur. To do.

  As used herein, the term “thin film resistance” means that gelatin capsules as described have a tendency to reduce film formation and show slowing, delaying or reduction of film formation even when stored under stress conditions. Means. Similarly, the term “inhibition of cross-linking” (or “inhibition of thin film formation”) refers herein to the relaxation of gelatin cross-linking (or thin film formation) as compared to similar capsule amounts that lack only the reagents provided by the present invention. Means deactivation, delay or decline.

  It has been found that the pharmaceutical dosage form according to the invention shows an unexpected and surprising substantial reduction in gelatin cross-linking and film formation in the capsule shell. As a result, such dosage forms can always meet desirable elution criteria in vitro, even after storage under stress conditions. The present invention provides significant improvements in conventional dosage forms and conventional capsule shells.

FIG. 1 shows the formation 30 tier after storage at 25 ° C. as described in Example 5.
It is a graph which shows I elution rate.

FIG. 2 shows the formation 30 tier after storage at 40 ° C. as described in Example 5.
It is a graph which shows I elution rate.

FIG. 3 shows the formation 30 tier after storage at 25 ° C. as described in Example 5.
It is a graph which shows II elution rate.

FIG. 4 shows the formation 30 tier after storage at 40 ° C. as described in Example 5.
It is a graph which shows II elution rate.

FIG. 5 shows the formation 19 Tier after storage at 25 ° C. as described in Example 5.
It is a graph which shows I elution rate.

FIG. 6 shows the formation 19 tier after storage at 40 ° C. as described in Example 5.
It is a graph which shows I elution rate.

FIG. 7 shows the formation 19 tier after storage at 40 ° C. as described in Example 5.
It is a graph which shows II elution rate.

Compositions suitable for the manufacture of capsule shells In one embodiment of the present invention, compositions suitable for the manufacture of capsule shells are provided. Such a composition according to the invention consists of gelatin and at least one sulfite compound present in an amount effective to inhibit gelatin shell crosslinking and / or film formation during storage.

  A “composition suitable for the manufacture of capsule shells” according to the present invention comprises gelatin, at least one sulfite compound, and any one or more excipients.

  Prior to using such a composition in the manufacture of gelatin capsule shells, a liquid, such as water, is usually added to the composition to form an aqueous mixture. In one embodiment, such a composition suitable for the manufacture of capsule walls consists of gelatin, at least one sulfite compound and water. Preferably the water is present such that the weight ratio of water to gelatin is from about 0.8 to about 1.6, more preferably from about 1 to about 1.3.

  Preferably, gelatin is present in the compositions of the present invention in an amount of from about 1 to about 99%, more preferably from about 10 to about 80%, and even more preferably from about 15 to about 90% of the composition on a dry weight basis. . The term “dry weight basis” should be understood to mean the total weight excluding the weight of water.

Sulphite Compound of the Composition Any pharmaceutically acceptable sulfite compound can be used in the composition of this embodiment. Exemplary pharmaceutically acceptable sulfite compounds include sodium metabisulfite, sodium bisulfite and sodium thiosulfate (sodium hyposulfite). One or more sulfite compounds are not more than about 10% total, for example about 0.01% to about 10%, preferably about 0.1, based on the dry weight of the composition in the composition of the present invention. % To about 5%, more preferably about 0.1% to about 2%.

Optional amines of the composition The compositions of the present invention can optionally include an amine reagent consisting of at least one pharmaceutically acceptable primary or secondary amine. Non-limiting examples of suitable primary amines include tromethamine (Tris), ethanolamine, diethylamine, ethylene N-methyl-D-glucamine and amino acids such as L-arginine, L-lysine and guanidine. Non-limiting examples of suitable secondary amines include diethanolamine, venetamine (ie, N- (phenylmethyl) benzeneethanamine), benzathine (ie, N, N-dibenzylethylenediamine), piperazine, hydrabamine (ie, N, N-bis (dehydroabiethyl) ethylenediamine) and imidazole. If desired, the amine compound is present in the composition of the present invention in an amount not more than about 10%, preferably not more than about 5%, more preferably not more than about 2.5%, based on the dry weight of the composition. Existing.

Optional excipients of the composition In addition to gelatin and the sulfite compound, the composition of the invention preferably further comprises one or more pharmaceutically acceptable excipients. When the composition of the present invention is used in the manufacture of soft gelatin capsules, the composition is at least about 2% to about 60%, preferably about 5% to about 45%, more preferably, based on the dry weight of the composition. Consists of about 10% to about 40% amount of, for example, at least one plasticizer. When a plasticizer is present, the plasticizer weight ratio (non-aqueous portion) is about 0.3 to about 1.8%, preferably about 0.4% to about 0.75% based on gelatin. . Non-limiting examples of suitable plasticizers include poly-hydroxy-alcohols such as sorbitol, glycerol and mannitol; dialkyl phthalates; lower alkyl citrates (lower alkyl has 1 to 6 carbon atoms); glycol And polyglycols, such as polyethylene glycol, methoxyl-propylene-glycol and 1,2-propylene glycol in the molecular weight range of about 200 to about 40,000; esters of polyhydroxy-alcohols such as mono-, di- and tri-acetates of glycerol; Lisinoleic acid and its esters; and mixtures thereof are included.

  The composition of the present invention further comprises one or more preservatives, an opacifying agent (for example, titanium dioxide), a decomposition inhibitor (for example, sulfur dioxide), a colorant, a flavor and the like. Non-limiting examples of suitable preservatives include methyl paraben, propyl paraben, butyl paraben, sorbic acid, benzoic acid, edetic acid, phenolic acid and sodium propionate.

  Suitable compositions for the manufacture of capsule walls can be in the form of a solid, dry powder, semi-solid, liquid solution or liquid suspension. It is important to note that the physical form (eg, powder, liquid mixture, etc.) of the composition of the present invention is at least in part, depending on the method used to make the capsule, if any It is determined by the type (hard or soft). One of ordinary skill in the art can readily select an appropriate physical form for the composition of the present invention in view of these and other factors.

Method for producing capsule of the present invention
i) Rigid Capsules Compositions of the present invention may be any suitable method described in, but not limited to, the patents and / or publications listed below, each incorporated herein by reference. Can be used to produce hard gelatin capsules.
Cordes US Patent 3,656,997.
US Patent 4,231,211 by Strampfer et al.
Voegle US Patent 4,263,251.
U.S. Pat. No. 4,403,461 to Goutard et al.
Lukas US Patent 4,705,658.
Hradecky et al., US Pat. No. 4,720,924.
US Patent 4,756,902 by Harvey et al.
US Patent 4,884,602 by Yamamoto et al.
Jones US Patent 4,892,766.
Sanso US Patent 6,350,468.
Mackie International Patent Publication WO 84/00919.
Kalidindi's international patent publication WO 85/04100.

  Those skilled in the art can readily adapt the methods described in the above references from the point of view of the present disclosure for the production of capsules containing the sulfite compounds according to the invention.

  One preferred method for producing the hard gelatin capsules of the present invention comprises: (a) preparing a composition (consisting of gelatin and a sulfite compound) suitable for the manufacture of a capsule shell in the form of a dry powder; and (b) water and composition. Preparing a liquid solution or solution / suspension consisting of an object, (c) heating the liquid, (d) immersing the stainless steel capsule manufacturing pin in the heated liquid, and (e) removing the immersed pin from the liquid. To form a coated pin, and (f) subject the coated pin to a drying step to produce a half shell of the dried capsule. After drying, the half shell of the capsule is removed from the pin and cut to the desired length. The half shell of the capsule is then filled with any desired filling material and combined together in a cooperative manner to form the capsule shell and then capped. The cap can optionally be spot welded, fused with molten gelatin or banded to provide a tamper resistant product. According to the method, the sulfite compound is preferably present in a composition suitable for the manufacture of capsule shells and / or optionally during steps (b), (c) and / or (d). It can also be added.

ii) Soft capsule The soft capsule of the present invention is preferably, but not limited to, a plate method, a vacuum method, or a rotary die method. For example, (1) Ansel et al., (1955) in Pharmaceutical Dosage Forms and Drug Delivery Systems, 6 th ed Williams & Wilkins, Baltimore, MD, 176-182 pages; and (2) Remington:. The Science and Practice of Pharmacy, 9 ^th Ed. Mack Publishing Co. Easton, PA, 1646–1647. The above pages are incorporated herein by reference.

  The rotary die method is the currently preferred method, and the soft gelatin capsules according to the present invention are produced by that method. According to the rotary die method, a composition comprising gelatin and a sulfite compound is dissolved or suspended in water to form a flowable material, which is then placed in an overhead tank. The flowable material from the overhead tank is formed into two continuous ribbons by a rotary die device, which is then combined with a pair of rotating dies. Simultaneously, the measured filling material is poured between the ribbons, and at approximately the same moment the die forms a ribbon pocket. These pockets containing the full encapsulant are then sealed with pressure and heat.

  Soft gelatin capsules can be produced in particular in round, oval, rectangular and tube shapes. In addition, two-tone capsules can be produced by using two different ribbons.

  Non-limiting examples of methods suitable for the production of soft gelatin capsules are described in the following patents and publications. Each is incorporated herein by reference.

Pesch's US Patent 3,592,945.
US Patent 4,609,403 by Wittwer et al.
Brox US Patent 4,744,988.
US Patent 4,804,542 to Fischer et al.
Herman US Patent 5,146,758.
US Patent 5,254,294 to Wunderlich et al.
Takayanagi's US Patent 6,260,332.
U.S. Patent 6,238,616 to Ishikawa et al.
Herman's international patent publication WO 92/15828.

  As used herein, the term “capsule shell” (and gelatin capsule shell) refers to a half shell of a capsule (which together forms the entire shell of the capsule, unless otherwise indicated in a particular situation). And the entire shell of the capsule (which defines the filling capacity of the capsule). Such terms also include soft gelatin capsule shells and hard gelatin capsule shells, respectively, according to the manner in which such shells are made.

  The terms “sealed capsule shell”, “seal in capsule shell”, “sealing in capsule shell” etc. mean the entire shell of the capsule which defines the filling volume, such filling volume being Contains filler material, such filler material is enclosed throughout the shell of the capsule, and such encapsulation provides a minimum protection from the outside air of the shell of the entire capsule.

Drugs with low water solubility The shells of the capsules according to the invention have a limited filling capacity, which can be occupied at least in part by the filling material. The filling material consists of any active drug. Preferably, the active drug is a drug with low water solubility, also referred to herein as a drug with poor water solubility. “Drug with low water solubility” or “drug with poor water solubility” as used herein has a solubility in water measured at 37 ° C. not greater than about 10 mg / mL, more preferably about 1 mg / mL By any drug or compound that is not larger. Particularly preferred are drugs whose solubility in water, measured at 37 ° C., is not greater than 0.1 mg / mL.

The solubility of many drugs in water is determined by standard pharmaceutical reference books such as The Merck Index, 11 ^th ed, 1989, published by Merck & Co. Inc., Rahway, NJ; The United States Pharmacopoenia, 24 ^th ed. (USP ), 2000;. the Extra Pharmacopoenia , 29 th ed 1989, Pharmaceutical Press published, London and Physicians Desk Reference (PDR), can be readily determined from the 2001 ed Economics Co. published, Montvale, NJ..

  For example, individual drugs with low solubility as defined herein are classified as “slightly soluble”, “very slightly soluble”, “virtually insoluble” and “insoluble” in USP 24, 225-2298. These drugs require 100 mL or more of water to dissolve 1 g of drug as listed in USP 24, 2299-2304.

Suitable low water solubility drugs include, but are not limited to, the following classes of drugs: abortion drugs, ACE inhibitors, alpha- and beta-adrenergic agonists, alpha- and beta-adrenergic antagonists, alpha -And β-adrenergic blockers, corticosteroids, adrenocorticotropic hormones, alcohol inhibitors, aldose reductase inhibitors, aldosterone antagonists, substance metabolizers, analgesics (including narcotic and non-narcotic analgesics), androgens , Angiotensin II receptor antagonist, anorexia pills, antacids, anthelmintics, anti-decubitus, anti-allergy, anti-hair loss, anti-amoeba, anti-androgen, anti-anginal, anti-arrhythmic, anti Atherosclerosis drugs, anti-arthritis / rheumatic drugs (including selective COX-2 inhibitors), anti-asthma drugs, anti-bacterial drugs, anti-bacterial adjuvants Anticholinergic, anticoagulant, anticonvulsant, antidepressant, antidiabetic, antidiarrheal, antidiuretic, antidote to poison, antidyskinesia, antieczema, antiemetic, antiestrogenic, antifiber Antihypertensive, antifungal, antiglaucoma, antigonadotropin, antigout, antihistamine, antihyperactivity, antihyperlipoproteinemia, antihyperphosphataemia, antihypertensive Antihyperthyroidism, antihypertensive, antihyperthyroidism, anti-inflammatory, antimalarial, antiepileptic, antimethroglobulinmic, antimigraine, antimuscarinic, anti Mycobacterial drugs, antineoplastic drugs and adjuvant drugs, antineutropenic drugs, osteoporosis drugs, anti-Paget drugs, anti-Parkinson drugs, anti-chromocytoma drugs, anti-pneumocystis drugs, anti-prostatic hypertrophy Medicine, antigenic animal medicine, antipruritic drug, anti Antiseptic, antipsychotic, antipyretic, antiricketia, antiseborrheic, antiseptic / antibacterial, antispasmodic, antisyphilis, antithrombocytic, antithrombotic, antitussive, antiulcer, Urine stone lysate, anti-snake toxin, antiviral, anxiolytic, aromatase inhibitor, astringent, benzodiazepine antagonist, bone resorption inhibitor, bradycardia, bradykinin antagonist, bronchodilator, calcium channel blocker, calcium Regulators, carbonic anhydrase inhibitors, cardiotonic agents, CCK antagonists, chelating agents, gallstone lytic agents, bile secretion promoting agents, cholinergic agents, cholinesterase inhibitors, cholinesterase reactivating agents, CNS stimulants, contraceptives, necrosis Tissue remover, decongestant, depigmentation, herpetic dermatitis inhibitor, digestive, diuretic, dopamine receptor agonist, dopamine Toner antagonist, ectoparasite eradication agent, emetic, enkephalinase inhibitor, enzyme, enzyme cofactor, estrogen, expectorant, fibrinogen receptor antagonist, fluorine compound replacement agent, gastric juice and pancreatic juice secretion stimulant, gastric cell protective agent , Gastric proton pump inhibitor, gastric secretion inhibitor, gastrointestinal motility regulator, glucocorticoid, α-glucosidase inhibitor, gonadal stimulating component, growth hormone inhibitor, growth hormone releasing factor, growth stimulator, blood increase Drug, Hematopoietic Promoter, Hemolytic, Hemostatic, Heparin Antagonist, Liver Enzyme Inducer, Hepatoprotectant, Histamine H ₂ Receptor Antagonist, HIV Protease Inhibitor, HMG CoA Reductase Inhibitor, Immune Modulator, Immunosuppressant, Insulin Sensitizer, ion exchange resin, keratolytic drug, breastfeeding stimulator , Laxatives / depressants, leukotriene antagonists, LH-RH agonists, fatty liver inhibitors, 5-lipoxygenase inhibitors, erythematous lupus suppressants, matrix metalloproteinase inhibitors, mineralocorticoids, miotics, monoamines Oxidase inhibitors, mucolytic agents, muscle relaxants, mydriatics, narcotic antagonists, neuroprotective agents, psychoactive agents, ovarian hormones, uterine contractors, pepsin inhibitors, pigmentation agents, plasma volume dilators, potassium channels Activator / opener, progestogen, prolactin inhibitor, prostaglandin, protease inhibitor, radiopharmaceutical, 5α-reductase inhibitor, respiratory stimulant, reverse transcriptase inhibitor, sedative / hypnotic, selenics, serotonin noradrenaline reactivation Uptake inhibitor, serotonin receptor agonist, cello Nin receptor antagonists, serotonin reuptake inhibitors, somatostatin analogs, thrombolytics agents, thromboxane A ₂ receptor antagonists, thyroid hormones, thyroid stimulating hormone, preventing preterm delivery agents, topoisomerase I and II inhibitors, uric acid excretion agents, vascular Vascular modulators, including vasodilators and vasoconstrictors, vasoprotectants, xanthine oxidase inhibitors and combinations thereof are included.

  Non-limiting examples of suitable drugs with low solubility include acetohexamide, acetylsalicylic acid, alclofenac, allopurinol, atropine, benzthiazide, carprofen, celecoxib, chlordiazepoxide, chlorpromazine, clonidine, codeine, codeine phosphate, codeine sulfate, Deracoxib, diacerein, diclofenac, diltiazem, estradiol, etodolol, etoposide, ettricoxib, fenbufen, fenclofenac, fenprofen, fenthiazac, flurbiprofen, gliocerfulvin, haloperidol, ibuprofen, indomethacin, indoprofen, ketoprofen , Lorazepam, medroxyprogesterone acetate, megestrol, methoxalane, methylpre Nizone, morphine, morphine sulfate, naproxen, nicergoline, nifedipine, niflumic, oxaprozin, oxazepam, oxyphenbutazone, paclitaxel, pheninedione, phenobarbital, piroxicam, pirprofen, prednisolone, prednisone, procaine, progesterone, dimethasulfidine, pyrexasulfazine Sulfisoxazole, sulindac, suprofen, temazepam, thiaprofenic acid, thyromizole, tolmetics, valdecoxib and the like.

  The amount of drug introduced into the filling material and filled into the capsules of the present invention can be selected according to known pharmaceutical ingredients. A therapeutically effective amount of drug is specifically contemplated. The term “therapeutically and / or prophylactically effective amount” as used herein means an amount of drug sufficient to induce a therapeutically and / or prophylactically required or desired response. Preferably, the therapeutic agent is present in an amount of at least about 0.01%, preferably at least about 0.1%, more preferably at least about 1%, and even more preferably at least about 5% by weight of the filler material. .

（式中、
Ａは、部分不飽和もしくは不飽和ヘテロシクリルおよび部分不飽和もしくは不飽和環状炭素環から選択される置換基であり、好ましくはピラゾリル、フラノニル、イソキサゾリル、ピリジニル、シクロペンテノニルおよびピリダジノニル基から選択されるヘテロシクリル基であり；
Ｘは、Ｏ、ＳまたはＣＨ₂であり；
ｎは０または１であり；
Ｒ¹は、ヘテロシクリル、シクロアルキル、シクロアルケニルおよびアリールから選択される少なくとも１個の置換基であり、置換可能な位置においてアルキル、ハロアルキル、シアノ、カルボキシル、アルコキシカルボニル、ヒドロキシル、ヒドロキシアルキル、ハロアルコキシ、アミノ、アルキルアミノ、アリールアミノ、ニトロ、アルコキシアルキル、アルキルスルフィニル、ハロ、アルコキシおよびアルキルチオから選択される１または２個以上の基で場合により置換され；
Ｒ²は、メチル、アミノまたはアミノカルボニルアルキルであり；
Ｒ³は、ヒドリド、ハロ、アルキル、アルケニル、アルキニル、オキソ、シアノ、カルボキシル、シアノアルキル、ヘテロシクリルオキシ、アルキルオキシ、アルキルチオ、アルキルカルボニル、シクロアルキル、アリール、ハロアルキル、ヘテロシクリル、シクロアルケニル、アラルキル、ヘテロシクリルアルキル、アシル、アルキルチオアルキル、ヒドロキシアルキル、アルコキシカルボニル、アリールカルボニル、アラルキルカルボニル、アラルケニル、アルコキシアルキル、アリールチオアルキル、アリールオキシアルキル、アラルキルチオアルキル、アラルコキシアルキル、アルコキシアラルコキシアルキル、アルコキシカルボニルアルキル、アミノカルボニル、アミノカルボニルアルキル、アルキルアミノカルボニル、Ｎ−アリールアミノカルボニル、Ｎ−アルキル−Ｎ−アリールアミノカルボニル、アルキルアミノカルボニルアルキル、カルボキシアルキル、アルキルアミノ、Ｎ−アリールアミノ、Ｎ−アラルキルアミノ、Ｎ−アルキル−Ｎ−アラルキルアミノ、Ｎ−アルキル−Ｎ−アリールアミノ、アミノアルキル、アルキルアミノアルキル、Ｎ−アリールアミノアルキル、Ｎ−アラルキルアミノアルキル、Ｎ−アルキル−Ｎ−アラルキルアミノアルキル、Ｎ−アルキル−Ｎ−アリールアミノアルキル、アリールオキシ、アラルコキシ、アリールチオ、アラルキルチオ、アルキルスルフィニル、アルキルスルホニル、アミノスルホニル、アルキルアミノスルホニル、Ｎ−アリールアミノスルホニル、アリールスルホニルおよびＮ−アルキル−Ｎ−アリールアミノスルホニルから選択される１またはそれ以上の基であり、Ｒ³はの置換可能な位置においてアルキル、ハロアルキル、シアノ、カルボキシル、アルコキシカルボニル、ヒドロキシル、ヒドロキシアルキル、ハロアルコキシ、アミノ、アルキルアミノ、アリールアミノ、ニトロ、アルコキシアルキル、アルキルスルフィニル、ハロ、アルコキシおよびアルキルチオから選択される１またはそれ以上の基で場合により置換され；
Ｒ⁴はヒドリドおよびハロから選択される）
の化合物である。 Selective COX-2 Inhibitor In a preferred embodiment, the drug is a selective cyclooxygenase-2 inhibitor. Preferred selective cyclooxygenase-2 inhibitors useful herein, or salts or prodrugs thereof useful herein which are converted thereto in vitro, are of formula (I):

(Where
A is a substituent selected from partially unsaturated or unsaturated heterocyclyl and partially unsaturated or unsaturated cyclic carbocycle, preferably a heterocyclyl selected from pyrazolyl, furanonyl, isoxazolyl, pyridinyl, cyclopentenonyl and pyridazinonyl groups A group;
X is O, S or CH ₂ ;
n is 0 or 1;
R ¹ is at least one substituent selected from heterocyclyl, cycloalkyl, cycloalkenyl and aryl, and in a substitutable position, alkyl, haloalkyl, cyano, carboxyl, alkoxycarbonyl, hydroxyl, hydroxyalkyl, haloalkoxy, Optionally substituted with one or more groups selected from amino, alkylamino, arylamino, nitro, alkoxyalkyl, alkylsulfinyl, halo, alkoxy and alkylthio;
R ² is methyl, amino or aminocarbonylalkyl;
R ³ is hydride, halo, alkyl, alkenyl, alkynyl, oxo, cyano, carboxyl, cyanoalkyl, heterocyclyloxy, alkyloxy, alkylthio, alkylcarbonyl, cycloalkyl, aryl, haloalkyl, heterocyclyl, cycloalkenyl, aralkyl, heterocyclylalkyl Acyl, alkylthioalkyl, hydroxyalkyl, alkoxycarbonyl, arylcarbonyl, aralkylcarbonyl, aralkenyl, alkoxyalkyl, arylthioalkyl, aryloxyalkyl, aralkylthioalkyl, aralkoxyalkyl, alkoxyaralkoxyalkyl, alkoxycarbonylalkyl, Aminocarbonyl, aminocarbonylalkyl, alkylaminocarbonyl, N-ali Ruaminocarbonyl, N-alkyl-N-arylaminocarbonyl, alkylaminocarbonylalkyl, carboxyalkyl, alkylamino, N-arylamino, N-aralkylamino, N-alkyl-N-aralkylamino, N-alkyl-N- Arylamino, aminoalkyl, alkylaminoalkyl, N-arylaminoalkyl, N-aralkylaminoalkyl, N-alkyl-N-aralkylaminoalkyl, N-alkyl-N-arylaminoalkyl, aryloxy, aralkoxy, arylthio, aralkyl Thio, alkylsulfinyl, alkylsulfonyl, aminosulfonyl, alkylaminosulfonyl, N-arylaminosulfonyl, arylsulfonyl and N-alkyl-N-arylaminosulfur One or more groups selected from phonyl, wherein R ³ is an alkyl, haloalkyl, cyano, carboxyl, alkoxycarbonyl, hydroxyl, hydroxyalkyl, haloalkoxy, amino, alkylamino, arylamino at the substitutable position of Optionally substituted with one or more groups selected from nitro, alkoxyalkyl, alkylsulfinyl, halo, alkoxy and alkylthio;
R ⁴ is selected from hydride and halo)
It is this compound.

［式中、
Ｒ⁵はメチルまたはアミノ基であり、Ｒ⁶は水素またはＣ_1-4アルキルもしくはアルコキシ基であり、Ｘ'はＮまたはＣＲ⁷（Ｒ⁷は水素またはハロゲンである）であり、ＹおよびＺは独立に、隣接した５または６員の環を定める炭素または窒素原子であり、１または２以上の位置において任意にオキソ、ハロ、メチルまたはハロメチル基で置換されていてもよい］
を有する選択性シクロオキシゲナーゼ−２阻害剤またはその異性体、互変異性体、医薬的に許容される塩もしくはプロドラッグである。好ましくは、このような５または６員の環は、１個の置換基で置換されるシクロペンテノン、フラノン、メチルピラゾール、イソオキサゾールおよびピリジン環である。 The composition of the present invention has the formula (II):

[Where:
R ⁵ is a methyl or amino group, R ⁶ is hydrogen or a C _1-4 alkyl or alkoxy group, X ′ is N or CR ⁷ (R ⁷ is hydrogen or halogen), Y and Z are Independently, a carbon or nitrogen atom defining an adjacent 5- or 6-membered ring, optionally substituted with an oxo, halo, methyl or halomethyl group at one or more positions]
Or a isomer, tautomer, pharmaceutically acceptable salt or prodrug thereof. Preferably, such 5- or 6-membered rings are cyclopentenone, furanone, methylpyrazole, isoxazole and pyridine rings substituted with one substituent.

  Illustratively, the capsule of the present invention comprises celecoxib, deracoxib, valdecoxib, rofecoxib, etoroxib, 2- (3,5-difluorophenyl) -3,4- [4- (methylsulfonyl) phenyl] -2-cyclopentene- 1-one, 2- (3,4-difluorophenyl) -4- (3-hydroxy-3-methyl-1-butoxy) -5- [4- (methylsulfonyl) phenyl] -3- (2H) -pyridazinone Suitable for delivering pharmaceutically acceptable salts and prodrugs thereof.

（式中、Ｘ"はＯ、ＳまたはＮ−低級アルキルであり；Ｒ⁸は低級ハロアルキルであり；Ｒ⁹は水素またはハロゲンであり；Ｒ¹⁰は水素、ハロゲン、低級アルキル、低級アルコキシまたはハロアルコキシ、低級アラルキルカルボニル、低級ジアルキルアミノスルホニル、低級アルキルアミノスルホニル、低級アラルキルアミノスルホニル、低級ヘテロアラルキルアミノスルホニルまたは５もしくは６員の窒素含有ヘテロシクロスルホニルであり；Ｒ¹¹およびＲ¹²は独立に水素、ハロゲン、低級アルキル、低級アルコキシ、またはアリールである）を有する化合物ならびにその医薬的に許容される塩のためにも有用である。 The capsules of the invention also have the formula (III):

Wherein X ″ is O, S or N-lower alkyl; R ⁸ is lower haloalkyl; R ⁹ is hydrogen or halogen; R ¹⁰ is hydrogen, halogen, lower alkyl, lower alkoxy or haloalkoxy Lower aralkylcarbonyl, lower dialkylaminosulfonyl, lower alkylaminosulfonyl, lower aralkylaminosulfonyl, lower heteroaralkylaminosulfonyl or 5- or 6-membered nitrogen-containing heterocyclosulfonyl; R ¹¹ and R ¹² are independently hydrogen, halogen , Lower alkyl, lower alkoxy, or aryl) and pharmaceutically acceptable salts thereof.

  Particularly useful compounds of the formula (III) are (S) -6,8-dichloro-2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid, in particular its water-soluble salts, such as the sodium salt It is a form.

Where the drug is celecoxib, the dosage form is usually therapeutic and / or dosage unit.
Or a total prophylactically effective amount of about 10 mg to about 1000 mg of celecoxib. When the drug is a selective COX-2 inhibitor other than celecoxib, the amount per dose unit is therapeutically equivalent to about 10 mg to about 1000 mg of celecoxib.

  It should be understood that a therapeutically and / or prophylactically effective amount of a drug for a subject depends in particular on the weight of the subject. A “subject” to which a therapeutic agent or composition thereof can be administered herein includes human patients of both sexes and any age, and also includes non-human animals, particularly household or companion animals such as cats, dogs or horses. The

  If the subject is a child or a small animal (eg, a dog), for example, a relatively low dose of a preferred range of amounts of about 10 mg to about 1000 mg appears to provide therapeutic efficacy. If the subject is a human adult or large animal (eg, a horse), it appears that a unit dose containing a relatively large amount of celecoxib is required to be therapeutically effective. A therapeutically effective amount in dosage forms of the invention in human adults is usually about 10 mg to about 400 mg of celecoxib per unit dose. Particularly preferably, the amount of celecoxib per unit dose is from about 100 mg to about 200 mg, such as about 100 mg or about 200 mg.

  For other selective COX-2 inhibitor drugs, the amount per dose unit can be in the range known as the therapeutically effective amount of such drugs. Preferably, the amount per dose unit is in a range that provides a therapeutic effect comparable to the celecoxib dose range indicated immediately above.

Liquid Filled Capsule In a preferred embodiment, the capsule of the present invention is filled with a liquid filling material. More preferably, the filling material self-emulsifies when contacted with simulated gastric fluid. The filler material in this embodiment consists of at least one tumor solvent suitable for dissolving the drug and / or any additional ingredients or excipients added thereto.

i) Glycol solvents Preferred solvents are glycols or glycol ethers. Suitable glycol ethers include formula (X):
R ¹ —O — ((CH ₂ ) _m O) _n —R ² (X)
Wherein R ¹ and R ² are independently hydrogen or C _1-6 alkyl, C _1-6 alkenyl, phenyl or benzyl group, but one R ¹ and R ² is hydrogen and m is 2 To an integer of about 5 and n is an integer of 1 to about 20. One of R ¹ and R ² is preferably a C _1-4 alkyl group, and the other is preferably hydrogen or a C _1-4 alkyl group, more preferably one of R ¹ and R ² is at least a methyl or ethyl group. is there. m is preferably 2. n is preferably an integer of 1 to about 4, and more preferably 2.

  The glycol ether used as a solvent in the filler material is typically about 75 to about 1000, preferably about 75 to about 500, more preferably about 100 to about 300. The important point is that the glycol ether used in the filling material of this embodiment is pharmaceutically acceptable and meets all other conditions described herein.

Non-limiting examples of glycol ethers used in the filler material of this embodiment include ethylene glycol monomethyl ether, ethylene glycol dimethyl ether, ethylene glycol monoethyl ether, ethylene glycol diethyl ether, ethylene glycol monobutyl ether, ethylene glycol dibutyl ether , Ethylene glycol monophenyl ether, ethylene glycol monobenzyl ether, ethylene glycol monobutyl phenyl ether, ethylene glycol triphenyl ether, diethylene glycol monomethyl ether, diethylene glycol dimethyl ether, diethylene glycol monoethyl ether, diethylene glycol diethyl ether, diethylene glycol divinyl ether, ethylene glycol Over mono butyl ether, ethylene glycol dibutyl ether, diethylene glycol isobutyl ether, triethylene glycol dimethyl ether, triethylene glycol monoethyl ether, triethylene glycol monobutyl ether include tetraethylene glycol monomethyl ether and mixtures thereof. For example, Flick (1998):. Industrial Solvent Handbook, 5 th ed Noyes Data Corporation, Westwood, see NJ. A particularly suitable glycol monoethyl ether solvent is diethylene glycol monoethyl ether, sometimes referred to in the art as DGME or ethoxydiglycol. It is commercially available, for example, under the trade name Transcutol® from Gattefosse Corporation.

  Glycols suitable as solvents for the filler material include propylene glycol, 1,3-butanediol and propylene glycol. The currently preferred solvent is propylene glycol (PEG).

  Any pharmaceutically acceptable PEG can be used. Preferably, the PEG has an average molecular weight of about 100 to about 10,000, more preferably about 100 to about 1,000. Preferably, PEG is liquid grade. PEGs that can be used in the liquid solvent of the present invention include PEG-200, PEG-350, PEG-400, PEG-540 and PEG-600. For example, see Flick (1998): supra, page 392. Presently preferred PEG has an average molecular weight of about 375 to about 450, such as 450-, as exemplified by PEG-400.

  PEG, such as PEG-400, has many desirable properties as a solvent for drugs that exhibit poor solubility in water. In the case of celecoxib, for example, the drug is dissolved or solubilized in very high concentrations in PEG-400, allowing the formulation of therapeutically effective doses in very small volumes of solvent liquid. When the resulting solution is encapsulated, drugs such as celecoxib, which require a relatively high dose for efficacy, can produce capsules of convenient size for swallowing that contain a therapeutically effective dose Is particularly important. Importantly, ethanol, water and other excipients identified below or elsewhere as co-solvents can optionally be used as solvents in the filling material of the present invention. Usually, one or more solvents are present in the filler material in a total amount of about 5 to about 95%, preferably about 10 to about 90%, more preferably about 15 to about 85%, based on the weight of the filler material. It will be.

ii) Cosolvent The filler material of this embodiment optionally consists of one or more pharmaceutically acceptable cosolvents. Non-limiting examples of suitable co-solvents include additional glycols, alcohols such as ethanol and n-butanol; olein and linoleic acid triglycerides such as soybean oil; capryl / capric acid triglycerides such as Mullyol® 812 from Huls; Capryl / capric acid mono- and diglycerides such as Abitec's Capmul® MCM; polyoxyethylene capryl / capric acid glycerides such as polyoxyethylene (8) capryl / capric acid mono- and diglycerides such as Gattefosse's Labrsola®; Propylene glycol fatty acid esters such as propylene glycol laurate; polyoxyethylene (35) castor oil such as Cremophor® EL from BASF; polyoxyethylene glyceryl trioleate such as Goldschmidt Tagat®; fatty acid lower alkyl esters such as butyric acid ethyl ester, caprylic acid ethyl ester and oleic acid ethyl ester; and water.

Filling material
When providing an amine reagent pharmaceutical dosage form, an amine reagent comprising at least a primary or secondary amine can be further added to the filler material disposed in the capsule of the present invention. Any pharmaceutically acceptable primary or secondary amine can be used as described above (for any amine reagent of the composition of the invention). Where the filling material consists of primary or secondary amine compounds, preferably such amine compounds are not therapeutically or nutritionally active. In a preferred embodiment, about 50% of any primary or secondary amine compound is present in the filler material, preferably at least about 55%, more preferably at least about 60%, and even more preferably at least about 65%. .

Sulphite Compound The filler material disposed in the capsules of the present invention can further be present with a sulfite compound as described herein above. In a preferred embodiment, at least about 40%, preferably at least about 50%, even more preferably at least about 55%, even more preferably at least about 60% of all sulfite compounds present in the dosage unit of the present invention. Even more preferably, at least about 70% is present in the capsule shell.

Sulphite Compound and Amine Reagent In accordance with the disclosure herein, it should be understood that in the dosage form of the present invention, the capsule shell comprises at least one primary or secondary amine and any sulfite compound. The filling material in this dosage form optionally comprises (1) at least one primary or secondary amine, or (2) a sulfite compound, or (3) at least one primary or secondary amine and It consists of any sulfite compound. Further, “at least a primary amine or secondary amine” means the presence of one or more primary amines, one or more secondary amines and a combination of primary and secondary amines. Should be understood as intended.

Other Excipient Filling Materials The filling material of the present invention optionally further comprises an antioxidant that removes at least one pharmaceutically acceptable free radical. Antioxidants that remove free radicals have the opposite meaning to “non-free radical removing antioxidants”, that is, antioxidants that do not have the ability to remove free radicals. Non-limiting examples of suitable free radical scavenging antioxidants include α-tocopherol (vitamin E), ascorbic acid (vitamin C) and its salts such as sodium ascorbate, ascorbyl palmitate, butylated hydroxyanisole (BHA) Butylated hydroxytoluene (BHT), fumaric acid and its salts, hyporic acid, malic acid, gallic acid alkyl esters such as gallic acid propyl ester, gallic acid octyl ester and gallic acid lauryl ester, sodium sulfite, sodium bisulfite and meta heavy There is sodium sulfite. Preferred free radical scavenging antioxidants are gallic acid alkyl esters, vitamin E, BHA and BHT. More preferably, the at least one free radical scavenging antioxidant is propyl gallate.

  One or more free radical scavenging antioxidants are optionally present in a total effective amount in the dosage form of the present invention so as to substantially reduce the added compounds in the formulation. Usually from about 0.01% to about 5%, preferably from about 0.01% to about 2.5%, more preferably from about 0.01 to about 1%, based on the weight of the filler material.

  The filling material according to the invention optionally consists of one or more pharmaceutically acceptable sweeteners. Non-limiting examples of suitable sweeteners include mannitol, propylene glycol, sodium saccharin, acesulfame K, neotame and aspartame. Alternatively or in addition, it is possible to use viscous sweeteners such as sorbitol solutions, syrups (sucrose solutions) or high fructose corn syrups, which in addition to the sweetening effect increase the consistency and Useful for delaying.

  The filling material according to the present invention optionally comprises one or more preservatives other than pharmaceutically acceptable free radical scavenging antioxidants. Non-limiting examples of suitable preservatives include benzalkonium chloride, benzethonium chloride, benzyl alcohol, chlorobutanol, phenol, phenylethyl alcohol, phenyl mercuric nitrate, thimerosal, and the like.

  The filling material according to the invention optionally consists of one or more wetting agents. Surfactants, hydrophilic polymers and certain clays are useful as wetting agents to aid in the elution and / or dispersion of hydrophobic drugs such as celecoxib. Non-limiting examples of suitable surfactants include benzalkonium chloride, benzethonium chloride, cetylpyridinium chloride, dioctyl sodium sulfosuccinate, nonoxynol 9, nonoxynol 10, noxinol 9, polyoxamer, polyoxyethylene (8) capryl / Capric mono- and ditriglycerides (eg Gattefosse Labrsola®, polyoxyethylene (35) castor oil, polyoxyethylene (20) cetostearyl ether, polyoxyethylene (40) hydrogenated castor oil, polyoxy Ethylene (10) oleyl ether, polyoxyethylene (40) stearate, polysorbate (20), polyoxysorbate (40), polyoxysorbate (60), polyoxysorbate 80 (eg ICI's Tween® 80), propylene glycol Ruraureto (e.g. Gattefosse in Lauroglycol (R)), sodium lauryl sulfate, sorbitan monolaurate, sorbitan monooleate, sorbitan monopalmitate, sorbitan monostearate, tyloxapol, and mixtures thereof.

  Furthermore, the dosage forms of the present invention optionally comprise one or more pharmaceutically acceptable buffering agents, flavoring agents, coloring agents, stabilizers and / or thickeners. Buffers can be used to control the pH of the formulation, thereby modulating the solubility of the drug. Flavoring agents increase patient compliance by making the dosage form more palatable, and coloring agents make the appearance more aesthetic and / or distinguishable. Non-limiting examples of suitable colorants include D & C Red No. 33, FD & C Red No. 3, FD & C Red No. 40, D & C Yellow No. 10 and C Yellow No. 6. Is included.

Without being bound by drug elution and gelatin cross-linking theory, the inventors believe that gelatin cross-linking is due to the covalent binding of amino acid residues of gelatin to form an insoluble material. This process results from low levels of aldehyde coming into contact with gelatin. The crosslinking of gelatin capsules can impact the behavior of the product by delaying the release of the formulation (containing the active compound) from the capsule shell. Delayed release, on the other hand, affects the rate of absorption of the compound into the bloodstream and the clinical onset of action. “Relaxing” crosslinking does not necessarily have a significant impact on the release of the formulation from the dosage form, whereas “strong” crosslinking has a significant impact. If the cross-linking is strong, in humans, there will be a delay in the release of the formulation from the dosage form, potential bioequivalence problems and a possible delay in clinical initiation of action.

  The capsules of the present invention are believed to exhibit reduced cross-linking (and thin film formation) of gelatin capsules, and therefore are more stressed than conventional capsules when filled with drug-containing compositions and subjected to in vitro dissolution assays. The change in elution rate during storage in can be advantageously reduced. The capsules of the present invention are also believed to exhibit more uniformity between the drug elution rates between the capsules than with standard gelatin capsules.

Without being bound by theory, the present inventors are convinced that the crosslinking of gelatin occurs by a process in which the amino acid residues of gelatin are covalently bonded to form an insoluble substance. This process results from low levels of aldehyde coming into contact with gelatin. Crosslinking of gelatin capsules can impact the behavior of the product by delaying the release of the formulation (containing the active compound) from the capsule shell. Delayed release, on the other hand, affects the rate of absorption of the compound into the bloodstream and the clinical onset of action. “Relaxing” crosslinking does not necessarily have a significant impact on the release of the formulation from the dosage form, whereas “strong” crosslinking has a significant impact. If the cross-linking is strong, in humans, there will be a delay in the release of the formulation from the dosage form, potential bioequivalence problems and a possible delay in clinical initiation of action.

  The capsules of the present invention are believed to exhibit reduced cross-linking (and thin film formation) of gelatin capsules, and therefore are more stressed than conventional capsules when filled with drug-containing compositions and subjected to in vitro dissolution assays. The change in elution rate during storage in can be advantageously reduced. The capsules of the present invention are also believed to exhibit more uniformity between the drug elution rates between the capsules than with standard gelatin capsules.

The following non-limiting examples are for illustrative purposes only and are not intended to be limiting. Example 1
The liquid fill formulation (F0) is prepared as shown in Table 1.

Example 2
Several compositions suitable for the preparation of capsule walls C1-C14 are prepared as shown in Tables 2 and 3 according to the following procedure. Gelatin and one or more sulfite compounds are mixed together to form a dry mixture. Then one or more plasticizers (glycerol and / or sorbitol) and water are added to the mixture to form a liquid mixture. The liquid mixture is melted at 80 ° C. for up to 4 hours to form a melt. The melt is cooled to 60 ° C. to form a flowable gelatin mixture which is fed to the two spreader boxes of the rotary die soft gelatin capsule making machine to control the flow of the mixture to the two air drying rotary drums. Two white transparent gelatin ribbons are extruded and processed into two white transparent gelatin capsules at a rate of about 15,000 capsules per hour, and the capsules are filled with 1 mL of the formulation FO of Example 1. The capsules are dried by blowing air at 21 ° C. and 20% relative humidity in a tumbler dryer, and then returned to room temperature.

  Several comparative compositions (no sulfite compound) (CC1-CC7) are prepared as described immediately above. It has the composition shown in Table 4.

  Filled capsules are stored at 40 ° C. and 75% relative humidity for up to 24 weeks. After 24 weeks storage, each capsule is analyzed for film formation. In general, capsules prepared from compositions C1-C14 (consisting of a sulfite compound) show less film formation than capsules prepared from comparative compositions CC1-CC7 (no sulfite compound).

Example 3
Two fill formulations, F1-F2, were prepared as shown in Table 5. 1 mL of each filling formulation was filled into several standard (no sulfite compound on the wall) soft gelatin capsules (RPScherer).

  Filled capsules were placed in sealed containers and stored at 40 ° C. and 75% relative humidity for up to 24 weeks. The capsules were removed from the sealed container at various times during storage, and the presence or absence of thin film formation (ie, crosslinking) was evaluated by visual inspection. Each evaluated capsule was assigned a numerical display based on the observed film. The score was as follows. (1) = No thin film; (2) = Thin imperfect film; (3) = Thin perfect film; (4) = Strong perfect film that hinders capsule compression; (5) = Thick, strong and It is a dense thin film. The observation of the thin film is shown in Table 6.

  As shown in Table 6, capsules containing the fill formulation F1 (consisting of about 3% by weight sodium metabisulfite in the amount of the fill material) showed no thin film formation when stored for 6 months. In contrast, fill formulation F2 (without sulfite compound) showed film formation by storage 15 and 30 days, respectively.

Example 4
The composition of the present invention is in a container: (a) 35% B grade, 150 Bloom power pharmaceutical gelatin; (b) 15% ice-cold glycerol; (c) 5% sodium thiosulfate) and (d) 45% Prepare a mixture of ice-cold deionized water. The mixture is melted at 80 ° C. for up to 4 hours to form a melt. The melt is cooled to 60 ° C. to form a flowable gelatin mixture which is fed to the two spreader boxes of the rotary die soft gelatin capsule making machine to control the flow of the mixture to the two air drying rotary drums. Two white transparent gelatin ribbons are extruded and processed at a rate of about 15,000 capsules per hour. Next, the capsules are dried by blowing air at 21 ° C. and 20% relative humidity in a tumbler dryer, and then returned to room temperature.

Example 5
The crosslinking behavior of the two soft gelatin formulations was studied over a 6 month period. As shown below (Table 7), formulation 30 (control lot) contains dimethylaminoethanol (DMAE) but no sulfite compound. Formula 19 (test lot) is the same as Formula 30 except that the filling material further contains sodium metabisulfite.

  Both gelatin capsule formulations were placed in non-derivatized hydroxypropylethylene bottles, sealed and stored at either 25 ° C. and 60% RH or 40 ° C. and 75% RH. Using such a bottle, the RH inside the bottle and the RH outside the bottle easily reached equilibrium (60% or 75%). Capsules were periodically examined with soft gelatin samples and evaluated by drug release profiles.

Formulation 30 . The release results of Tier I drug for control formulation 30 at 25 ° C / 60% relative humidity (RH) and 40 ° C / 75% relative humidity (RH) are shown in FIGS. 1 and 2, and the release results of Tier II drug are shown in FIGS. 4 shows. As early as 1 month of storage, there was a significant delay in the Tier I drug release profile at both temperature conditions. This delay increased with storage time. The Tier II drug release profile at 25 ° C./60% RH and 40 ° C./75% RH showed a significant but significant decrease in the release profile.

Formulation 19 . The release result of the Tier I drug under the condition of 25 ° C./60% RH in Formulation 19 is shown in FIG. No change in drug release profile was observed over 6 months, indicating that no crosslinking occurred. Therefore, the same Tier II test was not performed on this sample. FIG. 6 shows the results for Tier I at 40 ° C./75% RH for Formulation 19. There was no change in the drug release profile at most stable time points, except at 6 months. A Tier II test was performed on this sample to determine if the change in drug release profile at 6 months was a result of crosslinking. The results of Tier II are shown in Figure 7. The results for Tier I and Tier II in this 6 month sample are very similar, indicating that the change in drug release profile is not due to cross-linking.

  These data indicate that Formula 30 had strong crosslinking. Changes in the Tier II drug release profile (ie, reduced delay) indicate that the Tier release delay is a result of crosslinking in this formulation, and also in the human case a significant delay in the drug release profile Is. Formulation 19 containing sodium metabisulfite shows no measurable cross-linking over 6 months, even under severe conditions (40 ° C./75% RH). These data demonstrate that the addition of sodium metabisulfite to this formulation significantly reduces the rate of crosslinking and completely prevents crosslinking. Without being bound by theory, it is believed that cross-linking is inhibited by the process in which sodium metabisulfite reacts with aldehydes to form bisulfite addition products. That is, sodium metabisulfite effectively removes aldehydes and renders them unavailable for promoting gelatin cross-linking.

Example 6
Four soft gelatin celecoxib formulations were prepared as shown in Table 8 and tested for thin film formation at 40 ° C. and 75% relative humidity (RH).

  In the absence of sulfite compounds, complete film formation was observed after only 2 weeks when stored at 40 ° C./75% RH (formulation 30, cross-linking score = 3).

  Tris (Formulation 20) at a concentration of 5 mg / g in the formulation delayed film formation after 1.5 months of storage at 40 ° C./75% RH, but was insufficient to prevent complete film formation. (Bridge rating = 3).

  The higher Tris concentration in the formulation (26 mg / g, Formula 50) completely prevented gelatin cross-linking upon 6 months storage at 40 ° C./75% RH.

A low sodium metabisulfite (SMB) concentration of 4 mg / g in the formulation (Formulation 19) appeared to be sufficient to prevent thin film formation when stored at 40 ° C./75% RH for 2 months.

Example 7
To obtain insight into the mechanism by which Tris (hydroxymethylaminomethane) in the filling material of gelatin capsules prevents thin film formation, a dosage form (formulation X-60 listed in Table 9) was prepared and as shown in Table 10 Stored under two different conditions. The capsules were removed at the indicated times and the filling material and the Tris content in the capsules were quantified. As shown in Table 10, with the passage of storage time, the Tris content in the capsule increased and the Tris content in the filling material decreased compared to the initial formulation.

FIG. 6 is a graph showing the Tier 30 elution rate of Formulation 30 after storage at 25 ° C. as described in Example 5. FIG. FIG. 6 is a graph showing the Tier 30 elution rate of Formulation 30 after storage at 40 ° C. as described in Example 5. FIG. FIG. 6 is a graph showing the Tier 30 elution rate of Formulation 30 after storage at 25 ° C. as described in Example 5. FIG. FIG. 6 is a graph showing the Tier 30 elution rate of Formulation 30 after storage at 40 ° C. as described in Example 5. FIG. FIG. 5 is a graph showing the tier I dissolution rate of Formulation 19 after storage at 25 ° C. as described in Example 5. FIG. FIG. 6 is a graph showing the Tier 19 elution rate of Formulation 19 after storage at 40 ° C. as described in Example 5. FIG. FIG. 5 is a graph showing the Tier II elution rate of Formulation 19 after storage at 40 ° C. as described in Example 5. FIG.

Claims (33)

  A composition comprising gelatin and a pharmaceutically acceptable sulfite compound and suitable for the manufacture of a capsule shell for pharmaceutical use.   The composition of claim 1 wherein the sulfite compound is present in an amount effective to inhibit gelatin cross-linking and / or film formation in a capsule shell prepared from the composition.   The composition of claim 1, wherein the sulfite compound is selected from the group consisting of sodium metabisulfite, sodium thiosulfate, and sodium bisulfite.   The composition of claim 1, wherein the sulfite compound is present in an amount not greater than about 10% of the composition on a dry weight basis.   The composition of claim 1, wherein the sulfite compound is present in an amount not greater than about 5% of the composition on a dry weight basis.   The composition of claim 1, wherein the sulfite compound is present in an amount not greater than about 2% of the composition on a dry weight basis.   The composition according to claim 1, further comprising at least one excipient selected from the group consisting of degradation inhibitors, opacifiers, preservatives, and plasticizers.   Furthermore, polyhydroxy-alcohol, ester of polyhydroxy-alcohol, dialkyl phthalate; lower alkyl citrate ester (lower alkyl has 1 to 6 carbon atoms), glycol, polyglycol, ricinoleic acid and ricinoleic acid ester The composition of claim 1 comprising a more selected plasticizer.   The composition of claim 1, further comprising a plasticizer selected from the group consisting of sorbitol, glycerol, propylene glycol and polyethylene glycol.    The composition of claim 1, further comprising a preservative selected from the group consisting of methylparaben, propylparaben, butylparaben, sorbic acid, benzoic acid, edetic acid, phenolic acid, sorbate and propionate.   The composition of claim 1 further comprising titanium dioxide.   The composition of claim 1 further comprising sulfur dioxide.   The composition of claim 1 in the form of a capsule shell.   14. The composition of claim 13, wherein the capsule shell determines the fill volume.   14. The composition of claim 13, wherein the capsule shell is a soft gelatin capsule shell.   15. The composition of claim 14, wherein the fill volume has a volume of about 0.1 to about 2 mL.   The composition of claim 16, wherein the fill volume has a volume of less than about 1 mL.   15. A composition according to claim 14, wherein the capsule shell is suitable for oral delivery of the drug contained in the filling volume.   The capsule shell contains a sulfite compound that is present in an amount sufficient to inhibit gelatin crosslinking and / or film formation in the capsule shell upon storage of the dosage form. A pharmaceutical dosage form comprising a filling material sealed to the surface.   20. A dosage form according to claim 19, wherein the filling material is a liquid.   21. The dosage form of claim 20, wherein the filling material is self-emulsifying when contacted with gastric juice.   The filler material comprises an amine reagent, the amine reagent comprising an amine comprising at least one pharmaceutically acceptable primary or secondary amine, wherein the amine reagent in the filler material is an amine in the capsule shell. 20. The dosage form of claim 19, wherein in combination with an agent, the dosage form is present in an amount effective to inhibit gelatin crosslinking and / or film formation in the capsule shell upon storage of the dosage form.   The filler material, in combination with an amine reagent in the capsule shell, is present in a pharmaceutically acceptable amount present in an amount effective to inhibit gelatin crosslinking and / or film formation in the capsule shell during storage of the dosage form. 20. The dosage form of claim 19, comprising a sulfite compound.   20. A dosage form according to claim 19, wherein the filling material comprises a drug.   The dosage form according to claim 24, wherein the drug has low water solubility.   25. The dosage form of claim 24, wherein the drug is a selective cyclooxygenase-2 inhibitor. The selective cyclooxygenase-2 inhibitor has the formula (I):

(Where
A is a substituent selected from partially unsaturated or unsaturated heterocyclyl and partially unsaturated or unsaturated cyclic carbocycle, preferably a heterocyclyl selected from pyrazolyl, furanonyl, isoxazolyl, pyridinyl, cyclopentenonyl and pyridazinonyl groups A group;
X is O, S or CH ₂ ;
n is 0 or 1;
R ¹ is at least one substituent selected from heterocyclyl, cycloalkyl, cycloalkenyl and aryl, and in a substitutable position, alkyl, haloalkyl, cyano, carboxyl, alkoxycarbonyl, hydroxyl, hydroxyalkyl, haloalkoxy, Optionally substituted with one or more groups selected from amino, alkylamino, arylamino, nitro, alkoxyalkyl, alkylsulfinyl, halo, alkoxy and alkylthio;
R ² is methyl, amino or aminocarbonylalkyl;
R ³ is hydride, halo, alkyl, alkenyl, alkynyl, oxo, cyano, carboxyl, cyanoalkyl, heterocyclyloxy, alkyloxy, alkylthio, alkylcarbonyl, cycloalkyl, aryl, haloalkyl, heterocyclyl, cycloalkenyl, aralkyl, heterocyclylalkyl Acyl, alkylthioalkyl, hydroxyalkyl, alkoxycarbonyl, arylcarbonyl, aralkylcarbonyl, aralkenyl, alkoxyalkyl, arylthioalkyl, aryloxyalkyl, aralkylthioalkyl, aralkoxyalkyl, alkoxyaralkoxyalkyl, alkoxycarbonylalkyl, Aminocarbonyl, aminocarbonylalkyl, alkylaminocarbonyl, N-ali Ruaminocarbonyl, N-alkyl-N-arylaminocarbonyl, alkylaminocarbonylalkyl, carboxyalkyl, alkylamino, N-arylamino, N-aralkylamino, N-alkyl-N-aralkylamino, N-alkyl-N- Arylamino, aminoalkyl, alkylaminoalkyl, N-arylaminoalkyl, N-aralkylaminoalkyl, N-alkyl-N-aralkylaminoalkyl, N-alkyl-N-arylaminoalkyl, aryloxy, aralkoxy, arylthio, aralkyl Thio, alkylsulfinyl, alkylsulfonyl, aminosulfonyl, alkylaminosulfonyl, N-arylaminosulfonyl, arylsulfonyl and N-alkyl-N-arylaminosulfur One or more groups selected from phonyl, wherein R ³ is alkyl, haloalkyl, cyano, carboxyl, alkoxycarbonyl, hydroxyl, hydroxyalkyl, haloalkoxy, amino, alkylamino, arylamino, nitro at the substitutable position Optionally substituted with one or more groups selected from: alkoxyalkyl, alkylsulfinyl, halo, alkoxy and alkylthio;
R ⁴ is selected from hydride and halo)
27. The dosage form of claim 26, wherein   Selective cyclooxygenase-2 inhibitors are celecoxib, delacoxib, valdecoxib, rofecoxib, etoroxib, 2- (3,5-difluorophenyl) -3- [4- (methylsulfonyl) phenyl] -2-cyclopenten-1-one, 2 -(3,4-difluorophenyl) -4- (3-hydroxy-3-methyl-1-butoxy) -5- [4- (methylsulfonyl) phenyl] -3- (2H) -pyridazinone, pharmaceutically 27. The dosage form of claim 26, selected from the group consisting of acceptable salts and prodrugs.   27. The dosage form of claim 26, wherein the selective cyclooxygenase-2 inhibitor is celecoxib.   The filler material further comprises at least one substance that promotes cross-linking of gelatin when in contact therewith, the substance being a drug or excipient, and the substance independently or other substance that promotes the cross-linking 25. A dosage form according to claim 24 which acts in combination with one or more. Including a shell of a first capsule and a second capsule, wherein the shells of the first and second capsules are substantially identical;
(A) testing the shell of the first capsule in a first in vitro dissolution assay;
(B) The second capsule shell is kept in a sealed container at 40 ° C. and 85% relative humidity for a period of 4 weeks, after this storage,
(C) when the shell of the second sealed capsule is tested in a second in vitro dissolution assay substantially the same as the first in vitro dissolution test;
The amount of drug eluting within 45 minutes in the second elution assay is within ± 15% of the amount of drug eluting within 45 minutes in the first elution assay, and where the first in vitro elution assay 31. The dosage form of claim 30, wherein the dosage form is carried out within a reasonably short time after the composition is manufactured.   And (a) at least one excipient selected from the group consisting of degradation inhibitors, opacifiers and preservatives, and (b) a plasticizer selected from the group consisting of sorbitol, glycerol, propylene glycol and polyethylene glycol Wherein the sulfite compound is selected from the group consisting of sodium metabisulfite, sodium thiosulfate and sodium bisulfite, and the sulfite compound is present in an amount not exceeding about 10% of the composition on a dry weight basis 20. A dosage form according to claim 19.   35. The dosage form of claim 32, wherein the filler material further comprises an amount of about 10 to about 400 mg of celecoxib.

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